The transcription factor Prox-1 is expressed in a number of tissues during embryonic development, including lens fiber cells, subpopulation of neurons in brains and neural tube, skeletal muscle, heart, liver, pancreas and lymphatic endothelial cells. Targeted inactivation of Prox-1 results in the defects of eye development because of the failure of lens fiber cells to elongate (Wigle et al., Nat. Genet. 21: 318-22, 1999). Prox-1 is also necessary for the migration of hepatocytes during liver development (Sosa-Pineda et al., Nat. Genet. 25: 254-5, 2000). In addition, Prox-1 deficient embryos lack lymphatic vasculature, while the blood vessel development is not affected (Wigle et al., Cell 98: 769-778, 1999).
Recently, others and we have demonstrated the essential role of Prox-1 in the regulation of the lymphatic endothelial phenotype. Overexpression of Prox-1 in blood vascular endothelial cells, where it is otherwise absent, leads to the increased expression of lymphatic endothelial markers and to the suppression of the genes characteristic for the blood vascular endothelial lineage (Petrova et al., Embo J. 21: 4593-9, 2002; Hong et al., Dev. Dyn. 225: 351-7, 2002).
Notch is a transmembrane protein that acts as a receptor in a cell-cell signaling mechanism, and in combination with other cellular factors, influences differentiation, proliferation and apoptotic events at all stages of development (Artavanis-Tsakonas, Science 284: 770-776, 1999). In animal models, mutations in the Notch receptor have resulted in developmental abnormalities (Joutel et al., Nature 383: 707, 1996; Li. et al., Nature Genet. 16:243, 1997).
Cancer treatments generally promote tumor regression by inhibiting tumor cell proliferation, inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) and/or prohibiting metastasis by reducing tumor cell motility or invasiveness. Colon cancers are a very common malignancy and colon cancers are typically adenocarcinomas, or sometimes carcinoid tumors. Treatment is primarily surgical resection of the colon, although chemotherapy has been found to be beneficial in some cases. These treatment options for colon cancer are of unpredictable and sometimes limited value, especially if the cancer has not been identified and removed at early stages. There continues to exist a need for novel therapies and diagnostic methods for cancer conditions.